BioVersys Works to Bring Antibiotic Resistance to an End

BioVersys, founded in 2008, is working on bringing a technology for screening and for the development of 'transcriptional regulator inhibiting compounds' (TRICs) to patients in order to overcome antibiotic resistance. The co-founders share their view on what makes successful scientists pursue a career as start-up entrepreneurs rather than a classic academic career. They describe the history and milestones of their company, and how their everyday work differs from that of peers in an academic or industrial research setting

The food additive vanillic acid controls transgene expression in mammalian cells and mice

Trigger-inducible transcription-control devices that reversibly fine-tune transgene expression in response to molecular cues have significantly advanced the rational reprogramming of mammalian cells. When designed for use in future gene- and cell-based therapies the trigger molecules have to be carefully chosen in order to provide maximum specificity, minimal side-effects and optimal pharmacokinetics in a mammalian organism. Capitalizing on control components that enable Caulobacter crescentus to metabolize vanillic acid originating from lignin degradation that occurs in its oligotrophic freshwater habitat, we have designed synthetic devices that specifically adjust transgene expression in mammalian cells when exposed to vanillic acid. Even in mice transgene expression was robust, precise and tunable in response to vanillic acid. As a licensed food additive that is regularly consumed by humans via flavoured convenience food and specific fresh vegetable and fruits, vanillic acid can be considered as a safe trigger molecule that could be used for diet-controlled transgene expression in future gene- and cell-based therapie

Dissecting Colistin Resistance Mechanisms in Extensively Drug-Resistant Acinetobacter baumannii Clinical Isolates

Nosocomial infections with; Acinetobacter baumannii; are a global problem in intensive care units with high mortality rates. Increasing resistance to first- and second-line antibiotics has forced the use of colistin as last-resort treatment, and increasing development of colistin resistance in; A. baumannii; has been reported. We evaluated the transcriptional regulator PmrA as potential drug target to restore colistin efficacy in; A. baumannii; Deletion of; pmrA; restored colistin susceptibility in 10 of the 12 extensively drug-resistant; A. baumannii; clinical isolates studied, indicating the importance of PmrA in the drug resistance phenotype. However, two strains remained highly resistant, indicating that PmrA-mediated overexpression of the phosphoethanolamine (PetN) transferase PmrC is not the exclusive colistin resistance mechanism in; A. baumannii; A detailed genetic characterization revealed a new colistin resistance mechanism mediated by genetic integration of the insertion element IS; AbaI; upstream of the PmrC homolog EptA (93% identity), leading to its overexpression. We found that; eptA; was ubiquitously present in clinical strains belonging to the international clone 2, and IS; AbaI; integration upstream of; eptA; was required to mediate the colistin-resistant phenotype. In addition, we found a duplicated IS; AbaI; -; eptA; cassette in one isolate, indicating that this colistin resistance determinant may be embedded in a mobile genetic element. Our data disprove PmrA as a drug target for adjuvant therapy but highlight the importance of PetN transferase-mediated colistin resistance in clinical strains. We suggest that direct targeting of the homologous PetN transferases PmrC/EptA may have the potential to overcome colistin resistance in; A. baumannii; IMPORTANCE; The discovery of antibiotics revolutionized modern medicine and enabled us to cure previously deadly bacterial infections. However, a progressive increase in antibiotic resistance rates is a major and global threat for our health care system. Colistin represents one of our last-resort antibiotics that is still active against most Gram-negative bacterial pathogens, but increasing resistance is reported worldwide, in particular due to the plasmid-encoded protein MCR-1 present in pathogens such as; Escherichia coli; and; Klebsiella pneumoniae; Here, we showed that colistin resistance in; A. baumannii; , a top-priority pathogen causing deadly nosocomial infections, is mediated through different avenues that result in increased activity of homologous phosphoethanolamine (PetN) transferases. Considering that MCR-1 is also a PetN transferase, our findings indicate that PetN transferases might be the Achilles heel of superbugs and that direct targeting of them may have the potential to preserve the activity of polymyxin antibiotics

The food additive vanillic acid controls transgene expression in mammalian cells and mice

Trigger-inducible transcription-control devices that reversibly fine-tune transgene expression in response to molecular cues have significantly advanced the rational reprogramming of mammalian cells. When designed for use in future gene- and cell-based therapies the trigger molecules have to be carefully chosen in order to provide maximum specificity, minimal side-effects and optimal pharmacokinetics in a mammalian organism. Capitalizing on control components that enable Caulobacter crescentus to metabolize vanillic acid originating from lignin degradation that occurs in its oligotrophic freshwater habitat, we have designed synthetic devices that specifically adjust transgene expression in mammalian cells when exposed to vanillic acid. Even in mice transgene expression was robust, precise and tunable in response to vanillic acid. As a licensed food additive that is regularly consumed by humans via flavoured convenience food and specific fresh vegetable and fruits, vanillic acid can be considered as a safe trigger molecule that could be used for diet-controlled transgene expression in future gene- and cell-based therapies

Monitoring Report 2002-2003

Quarterly average values of radioactivity levels in airborne particulates, surface water, drinking water, milk and mixed diet are reported for the fifteen countries of the European Union (sparse and dense network) for the years 2002 - 2003.JRC.H.4-Transport and air qualit

Environmental Radioactivity in the European Community 2004-2006

Quarterly average values of radioactivity levels in airborne particulates, surface water, drinking water, milk and mixed diet are reported for the twenty five countries of the European Union (sparse and dense network) for the years 2004-2006.JRC.H.4-Transport and air qualit

The role of OmpR in bile tolerance and pathogenesis of adherent-invasive Escherichia coli

International audienceGut microbiota dysbiosis toward adherent-invasive Escherichia coli (AIEC) plays an important role in Crohn’s disease (CD). The OmpR transcriptional regulator is required for the AIEC LF82 prototype strain to adhere and invade intestinal epithelial cells. In this study, we explored the role of OmpR in AIEC pathogenesis using a panel of eight Escherichia coli strains isolated from CD patients and identified as AIEC. The deletion of ompR together with the implementation of two cell-based assays revealed that the role of OmpR in adhesion in vitro was not conserved in AIEC clinical strains. Nevertheless, we showed that OmpR was required for robust gut colonization of transgenic mice expressing human CEACAM receptors, suggesting that OmpR is involved in alternative virulence mechanisms in AIEC strains. We found that deletion of ompR compromised the ability of AIEC strains to cope with the stress induced by bile salts, which may be key for AIEC pathogenesis. More specifically, we demonstrated that OmpR was involved in a tolerance mechanism toward sodium deoxycholate (DOC), one of bile salts main component. We showed that the misregulation of OmpF or the loss of outer membrane integrity are not the drivers of OmpR-mediated DOC tolerance, suggesting that OmpR regulates a specific mechanism enhancing AIEC survival in the presence of DOC. In conclusion, the newly discovered role of OmpR in AIEC bile tolerance suggests that OmpR inhibition would interfere with different aspects of AIEC virulence arsenal and could be an alternative strategy for CD-treatment

A novel genome editing platform for drug resistant Acinetobacter baumannii revealed an AdeR-unrelated tigecycline resistance mechanism

Infections with the Gram-negative coccobacillus Acinetobacter baumannii are a major threat in hospital settings. The progressing emergence of multidrug resistant clinical strains significantly reduces the treatment options for clinicians to fight A. baumannii infections. The current lack of robust methods to genetically manipulate drug resistant A. baumannii isolates impedes research on resistance and virulence mechanisms in clinically relevant strains. In this study we developed a highly efficient and versatile genome editing platform enabling the markerless modification of the genome of A. baumannii clinical and laboratory strains, regardless of their resistance profile.We applied this method for the deletion of AdeR, a transcription factor that regulates the expression of the AdeABC efflux pump in tigecycline resistant A. baumannii, to evaluate its function as a putative drug target. Loss of adeR reduced the MIC90 of tigecycline from 25 μg/ml in the parental strains to 3.1 μg/ml in the ΔadeR mutants indicating its importance in the drug resistant phenotype. However, 60% of the clinical isolates remained non-susceptible to tigecycline after adeR deletion. Evolution of artificial tigecycline resistance in two strains followed by whole genome sequencing revealed loss of function mutations in trm, suggesting its role in an alternative AdeABC-independent tigecycline resistance mechanism. This finding was strengthened by the confirmation of trm disruption in the majority of the tigecycline resistant clinical isolates. This study highlights the development and application of a powerful genome editing platform for A. baumannii enabling future research on drug resistance and virulence pathways in clinical relevant strains